Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Physiology and Pharmacology

Supervisor

Dr. Peter Chidiac

Abstract

Stresses from the external environment can disrupt cellular processes and result in damaging effects, such as the misfolding of proteins, which have been linked to several diseases. Regulator of G protein signalling 2 (RGS2) is upregulated by several forms of stress and can inhibit protein synthesis, an established response to stress typically achieved via the phosphorylation of the initiation factor, eIF2, to conserve energy and resources. Under reduced translation, some factors are selectively expressed via alternative translation mechanisms and these factors consequently may promote apoptosis. The molecular mechanisms mediating such opposing responses to stress are not well understood. Here, we suggested that RGS2 may be an important regulatory component in the cellular stress response and we hypothesized that RGS2 contributes to the response of cells to stress through its translational control abilities. Previously, we have shown that RGS2 can interact with the translation initiation factor, eIF2B, and inhibit de novo protein synthesis. Here, we demonstrated that the expression of RGS2 decreased total protein levels and significantly increased levels of factors linked to stress-induced apoptosis such as ATF4 and CHOP. Interestingly, expression of the eIF2Bε-interacting domain of RGS2 (RGS2eb) alone resulted in a 20-fold increase in caspase 3 activation which was not seen with full-length RGS2. Furthermore, we showed that these effects are translationally regulated and independent of eIF2 phosphorylation. Thus, we present a novel mechanism in the regulation of stress response by RGS2. These results also suggest that RGS2 may be pro-apoptotic and may potentially be an important target in stress-related pathologies.


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